Animal models to study acute and chronic intestinal inflammation in mammals

Abstract

Acute and chronic inflammatory diseases of the intestine impart a significant and negative impact on the health and well-being of human and non-human mammalian animals. Understanding the underlying mechanisms of inflammatory disease is mandatory to develop effective treatment and prevention strategies. As inflammatory disease etiologies are multifactorial, the use of appropriate animal models and associated metrics of disease are essential. In this regard, animal models used alone or in combination to study acute and chronic inflammatory disease of the mammalian intestine paired with commonly used inflammation-inducing agents are reviewed. This includes both chemical and biological incitants of inflammation, and both non-mammalian (i.e. nematodes, insects, and fish) and mammalian (i.e. rodents, rabbits, pigs, ruminants, dogs, and non-human primates) models of intestinal inflammation including germ-free, gnotobiotic, as well as surgical, and genetically modified animals. Importantly, chemical and biological incitants induce inflammation via a multitude of mechanisms, and intestinal inflammation and injury can vary greatly according to the incitant and animal model used, allowing studies to ascertain both long-term and short-term effects of inflammation. Thus, researchers and clinicians should be aware of the relative strengths and limitations of the various animal models used to study acute and chronic inflammatory diseases of the mammalian intestine, and the scope and relevance of outcomes achievable based on this knowledge. The ability to induce inflammation to mimic common human diseases is an important factor of a successful animal model, however other mechanisms of disease such as the amount of infective agent to induce disease, invasion mechanisms, and the effect various physiologic changes can have on inducing damage are also important features. In many cases, the use of multiple animal models in combination with both chemical and biological incitants is necessary to answer the specific question being addressed regarding intestinal disease. Some incitants can induce acute responses in certain animal models while others can be used to induce chronic responses; this review aims to illustrate the strengths and weaknesses in each animal model and to guide the choice of an appropriate acute or chronic incitant to facilitate intestinal disease.

Keywords: Acute; Animal models; Biological; Chemical; Chronic; Incitants; Inflammation; Intestine.

Fig. 1

Systemic effects of intestinal inflammation. Multiple areas of the body can be influenced by intestinal inflammation. After stimulation occurs in the intestine, circulating macrophages stimulate the release of cytokines. These cytokines not only promote macrophage and dendritic cell recruitment, but also stimulate the hypothalamus to alter food intake and increase the rate of metabolic activity through adrenal gland stimulation by ACTH and the production of corticosterone. Simultaneously, cytokines stimulate muscles to promote amino acid usage that can influence the liver and bone marrow. Acute-phase proteins released by the liver also influence other cytokine production, and the intermingled cycle continues as the intestinal mucosa is stimulated. ACTH adrenocorticotropic hormone

Fig. 2

Small intestine mucosal immunity. Intestinal epithelial cells (IEC) make up the epithelial lining. The IEC are covered by mucus which serves as an important component of the innate immune system. In the large intestine mucus is divided into two distinct layers that vary in thickness ; the thicker outer layer being bacteria-rich and the thinner inner layer containing no or few bacteria  (not shown in image). The epithelium is composed of enterocytes and M cells, and these cells are held together by tight junction proteins. Of note, these cells and structures are also areas where bacteria can enter the host to induce inflammation and activate underlying immune cells. Cells important in immuno-surveillance, such as dendritic cells within the lamina propria can move through M cells or tight junctions in the IECs to sample luminal contents [28]. This information is presented to T-cell populations through the secretion of cytokines to facilitate cell maturation and proliferation [294]. Th1 (IFN-γ, IL-6, TNF-α) cytokines and Th17 (IL-17A, IL-22) cytokines activate pro-inflammatory responses, Treg (IL-10, TGF-β) cytokines are anti-inflammatory and Th2 (IL-4, IL-5, IL-13) cytokines have both anti-inflammatory and pro-inflammatory potential. Immunoglobulin A (IgA) is released from plasma cells at intestinal crypts while antimicrobial peptides (AMP) and defensins are released from Paneth cells (not shown) [28]. M cell microfold cell, TLR toll-like receptor, Th helper T-cell. Transcription factors; Foxp3 (Treg), T bet (Th1), Rorγt (Th17), Gata3 (Th2)

Fig. 3

Sheep intestinal loop model. Ovine ileal segments inoculated with a Campylobacter jejuni 81-176 or b phosphate buffered saline and harvested 48 h post inoculation. Campylobacter jejuni treated intestinal loops are markedly edematous, congested, and presented with numerous fibrino-hemorrhagic foci of mucosal necrosis